JP2003508765A - Method and apparatus for measuring blood characteristics including hemoglobin - Google Patents

Abstract

  (57) [Summary] Blood properties, including hemoglobin, are measured non-invasively from a mixture of liquid and blood cells in a light transmission tube, especially in human blood vessels, using two light beams of different wavelengths directed at the light transmission tube. . The ratio of the detection intensity of the reflected light of the light beam is calculated, and the blood characteristics are measured by analyzing the ratio.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to a non-invasive method for measuring blood characteristics (EVF / hematocrit) containing hemoglobin in a tube containing a mixture of liquid and blood cells using the effect of orienting red blood cells. is there. The invention also relates to a device for implementing the measuring method.

BACKGROUND ART Various non-invasive methods for measuring hemoglobin are known. These measuring methods utilize the absorption of light energy of red blood cells (RBCs) at a specific wavelength. US Pat. No. 5,755,226 to Karim et al. Discloses a non-invasive method and apparatus for non-invasive, direct prediction of hematocrit in mammalian blood using photoplethysmography (PPG) and data processing. However, the method only utilizes the ability of red blood cells to absorb energy, and
In the above method, the formula used when calculating the predicted hematocrit is extremely complicated. Therefore, the method is time consuming. Moreover, the above method does not consider the orientation and distribution of red blood cells in blood vessels.

Further, WO97 / 15229 discloses a method and an apparatus for measuring the hemoglobin concentration in blood. The method is used to introduce a measuring tip into the subject's mouth to detect hemoglobin in the microvasculature below the mucous membrane inside the subject's lips. This means that the measuring tip of the device must have some sterile shell before it can be put into the mouth. The sterility of the measuring tip means that the device must be autoclaved before the measurement or a disposable plastic tip must be used when carrying out the method. Further, the method utilizes light reflection to measure hemoglobin concentration.

Therefore, there is a need for a new method for detecting hemoglobin that takes into account the orientation of blood cells and provides a more accurate detection value. Furthermore, a method that does not require an extra step of sterilizing the device before measurement or a disposable tip is desirable. The new method should also be one that is less sensitive to fluctuations in blood pressure, eg pulsatile pressure (maximum blood pressure).

DISCLOSURE OF THE INVENTION The first aspect of the present invention relates to (a) the above-mentioned light-transmitting tube for measuring blood characteristics including hemoglobin from a mixture of a liquid and blood cells contained in the light-transmitting tube. First of different wavelengths
Directing a light beam and a second light beam, (b) detecting the light intensity of each of the first and second light beams reflected from the translucent tube, (c) calculating the ratio of the detected intensities, (d) A new non-invasive measurement method comprising the step of analyzing the ratio and measuring blood characteristics.

Analyzing the ratio of the detected intensities of the reflected light has the advantage that the effects from the pressure and flow rate of the liquid mixture, especially in the pulsatile flow, are compensated for and the measured blood properties are accurate. The ratio is analyzed by comparing it to the ratio previously obtained for the known value of the blood property in question.

A second aspect of the present invention is an apparatus for measuring blood characteristics containing hemoglobin from a mixture of a liquid and blood cells contained in a light-transmitting tube, wherein the first and the second wavelengths are different with respect to the light-transmitting tube. A first light source and a second light source for directing the light beam and the second light beam, at least one detector for detecting the light intensities of the first and second light beams reflected from the light-transmitting tube, respectively, and An apparatus comprising a processing device for calculating a ratio of detection intensities, analyzing the ratio, and measuring a blood characteristic.

The device may also optionally include a recording means for storing the value of the measured blood characteristic and / or
Alternatively, a means for visualizing the measured blood characteristic may be provided.

[0009]   A third aspect of the invention is the use of the device of the invention in a dialysis machine.

The term “light source” should be understood to include one or more light emitting devices such as photodiodes.

In the present application, the term “blood characteristics” refers to, for example, the concentration of blood components such as hemoglobin, total hemoglobin, red blood cells, white blood cells, platelets, cholesterol, albumin, thrombocytes, lymphocytes, drugs and other substances, It means characteristics of blood such as viscosity, blood pressure, blood flow, blood volume, blood cell disease, abnormal blood cell expression, anemia, leukemia or lymphoma.

In the present application, the term “hemoglobin” means total hemoglobin, oxyhemoglobin, reduced hemoglobin, carboxyhemoglobin, methemoglobin or sulfhemoglobin.

In the present application, when referring to “erythrocytes” is meant total or partially lysed erythrocytes containing hemoglobin.

In the present application, the term “light-transmitting tube” means a blood vessel, a pipe, a tube, or a tubular object that passes through blood vessels of animals, mammals, or humans. Pipe, tube or tubing is acrylonitrile butadiene styrene (ABS) which provides a non-flexible material
Polyvinyl chloride (PVC), silicone rubber, soft PVC, which may be made of polycarbonate or acrylic glass (polymethylmethacrylate; PMMA), and which provides a flexible material, such as dioctyl phthalate, diethylhexyl phthalate or It may be made from PVC plasticized with trioctyl trimellitate. PMM
A is the most preferred non-flexible material. The elasticity of the material may vary widely.

As used herein, “light” generally refers to electromagnetic radiation at any wavelength, including the infrared, visible, and ultraviolet regions of the spectrum. In this connection
Of particular interest is light in the spectral range, such as visible light and near-infrared light, which is capable of at least partially penetrating tissue. In the present invention, the light may include unpolarized light or polarized light, coherent light or incoherent light, and irradiation of the light-transmitting tube may be performed using a stationary light pulse, amplitude-modulated light or continuous light. Should be understood.

In the method according to the invention, the wavelength of the first light beam is chosen such that the light absorption of the red blood cells is relatively small when the first light beam passes through the red blood cells and the wavelength of the second light beam is It is preferable to choose so that the light absorption of the red blood cells is relatively high as they pass through the red blood cells.

The wavelength of each light beam is 200 nm to 2000 nm, preferably 400 nm to 1
It can be selected within the range of 500 nm. Specifically, the wavelength of the first light beam is 770 nm to 950 nm, that is, within the range of near infrared (NIR), preferably 770, 800, 850, 940 or 950 nm is selected, and the wavelength of the second light beam is selected. Is in the range of 480 nm to 590 nm, that is, green light, preferably 50
0 nm is selected.

The first and second light beams are oriented essentially perpendicular to the light-transmitting tube, and the intensities of the reflected light of the first and second light beams are respectively transmitted between the first and second light beams. It is appropriate to detect it on the pipe.

The steps (a) and (b) of the novel method may be performed while the mixture of liquid and blood cells is flowing through the translucent tube. This allows the method to be carried out on mammals, such as livestock or, more importantly, on humans, i.e. on light-transmitting tubes containing blood vessels. The vessel must have a diameter greater than 0.1 mm and should be a vein, artery or arteriole. Said blood vessel may suitably be a wrist, toe or finger blood vessel, preferably a wrist or third phalange finger blood vessel. Alternatively, steps (a) and (b) may be performed when the mixture is stationary, as is the case for liquid media in a blood bag assembly.

Even if the steps (a) and (b) are carried out in the tubing of an extracorporeal device including, for example, a dialysis device, a cell saver, a dialysis monitor, a slaughterhouse device or a blood collection device, It may be performed with a three-dimensional tube.

The values of the detection intensities of the reflected light of the first and second light beams are wireless, and preferably, by using a communication channel compliant with the Bluetooth (registered trademark) standard, steps (d) and (e) are performed. ) Is sent to the means.

In the device of the present invention, the first light source emits light of a wavelength that is basically not absorbed by red blood cells, and the second light source emits light of a wavelength that is basically absorbed by red blood cells.
Each light source is 200 nm to 2000 nm, preferably 400 nm to 1500 nm
It should emit light of a wavelength within the range. The wavelength of the light emitted by the first light source is within the range of 770 nm to 950 nm, preferably 770, 800, 850, 9
The wavelength of the light emitted by the second light source is 480 nm to 59 nm.
Within the range of 0 nm, preferably 500 nm.

The detector is suitably arranged between the first and second light sources and detects the intensity of the reflected light of the first and second light beams, respectively. The first and second light sources emit respective first and second light beams, respectively, essentially perpendicular to the tube.

The light source and detector are suitably incorporated into a laboratory device for non-invasive application to the blood vessels of mammals, preferably humans. The experimental device may have a shape that fits a wrist, a toe, or a finger. In particular, the laboratory device may comprise a thimble-like shell applied to the fingers or toes. The light source and detector may direct a light beam within the shell to detect the light intensity. The shell may form a contraction in which the detector and at least one first and second light source are arranged.

Communication means may be provided for wireless communication between various components of the device, including a light source, a detector, a processing device, and optionally a recording means and a visualization means. Preferably said communication means comprises a separate module for transmitting and receiving signals, said module comprising:
By using a Bluetooth (registered trademark) standard compliant communication path,
Signals can be sent and received.

The light source may be composed of a light emitting diode, in which case the distance between each diode and the detector is 4 to 12 mm, preferably 8 to 9 mm, as the distance between the centers of the diode and the detector. . The light emitting diode has the same shell, for example a chip
It may be incorporated in a (chip) or may be arranged on one side of the measurement target. The light emitting diodes may alternately illuminate when used simultaneously in a chip.

The processing apparatus appropriately performs steps (a) to (d) of the novel method. Further, the processing device may convert the detected intensity value into a concentration value of the measured blood characteristic.

In general, the light source used in the method and apparatus of the present invention may be a laser diode such as a vertical cavity surface emitting laser (VCEL) or a light emitting diode (LED).
It is preferable to use LEDs that are not very expensive. Currently, there are also new powerful light emitting diodes, which may be used. Strobes, quartz halogen lamps or tungsten lamps may also be used as the light source. Further, the light source may be one capable of emitting monochromatic light, i.e. a monochromator. The point to be measured of the light-transmitting tube may be directly illuminated or may be indirectly illuminated by guiding light through an optical fiber.

Suitable detectors for use in the method and apparatus of the present invention are phototransistors, photodiodes, photomultiplier tubes, photocells, photodetectors, optical power meters, amplifiers, CCD arrays and the like.

The mixture of liquid and blood cells may be composed of plasma or other liquid, for example water or dialysate. The plasma is preferably in or from a mammal. Further, the liquid may be another fluid containing blood cells obtained during or after the treatment of blood.

The light-transmitting tube, preferably the tube or pipe, should have a diameter greater than 0.1 mm. During dialysis, it is desirable to measure hemoglobin concentration to follow changes in the patient's blood volume. With respect to a blood bag assembly, steps (a) and (b) of the novel method include a whole blood or buffy coat, i.e., a tubular body, a bag, used in connection with a blood bag assembly containing leukocyte concentrates, a bag, It may also be done for filters or other components.

There are various other possible applications of the novel method. Therefore, the method also
It may be performed with blood transfusion through a tubular body or blood donation as well. In the slaughterhouse, the novel method is to collect blood from slaughtered livestock, and further process the collected blood to make whole blood for direct food or by separating blood components such as albumin and immunoglobulin. Is useful when getting The novel method may be used when counting blood cells, ie in the process of counting red blood cells and white blood cells. This may be done, for example, with a device such as a blood cell counter such as the Coulter Counter manufactured by Coulter Diagnostics, Inc. of Miami, Florida. Furthermore, the novel method may be used in connection with blood analysis, blood group determination or blood gas analysis. Further, the novel method may be used when separating human blood with a blood separating apparatus. It is desirable to use the new method when obtaining plasma from a donor. The novel method is also useful when obtaining a buffy coat from a blood donor or when the buffy coat is further processed to produce cytokines such as interferon alpha. Finally, the method of the present invention is also useful when obtaining a buffy coat from a blood donor or when this buffy coat is further processed to produce cytokines such as interferon alpha. For example, after one or more steps involving erythrocyte lysis with ammonium chloride, lysis of erythrocytes during purification of leukocytes exposed to virus, e.g., Sendai virus, during culture in a suitable medium, e.g., Eagles Minimal Essential medium. Is useful for measuring how much is done.

According to an embodiment of the present invention, at least 6 light beams are directed from 6 light sources to the transmissive tube, 3 of which emit near-infrared light and 3 of the remaining light sources are It emits green light. The intensity of infrared and green light reflected from the transparent tube is at least 1
Only one detector is detected, preferably only one detector.

By incorporating a cable-less communication device into the method and apparatus of the present invention to make it easier to use, the use of the novel method and apparatus is broadened. The cableless communication device allows for Internet billing, patient information review and statistics, software package updates and services. The user can obtain the code needed to perform multiple tests, just as they are done with a cellular phone.

The wireless communication standard Bluetooth (registered trademark) has provided the opportunity to use devices that do not require cables in hospitals. Bluetooth (Bluetooth,
The registered trademark technology allows electronic devices to communicate with each other without a cable. Bluetooth modules, which consist of a transmitter and a receiver, may replace cables for many applications. FIG. 13 shows a system comprising a computer and a blood characteristic detector, which system uses Bluetooth technology and does not require a cable between the computer and the detector.

Bluetooth (Bluetooth, registered trademark) developed by LM Ericsson
The technology may use the ISM band 2.45 GHz and also ensure uninterrupted communication. The system can work with fast frequency hopping of 1.600 hops per second. The output from the transmitter may be reduced to work at a maximum distance of 10 meters. However, the distance between the components capable of wireless communication of the device of the present invention can be changed from 1 cm to 10,000,000 miles.

The components (i) and (ii) may themselves form an independent entity, eg a handcuff-like or thimble-like device as described below. The handcuff or thimble device may further incorporate a transmitter that sends the signal to a receiver for processing the signal.

The components of the new device, including the photodiode and the detector, include (a) a flexible material, preferably a polymeric material, most preferably a flexible material proximate the components, ie the diode and the detector. A first part preferably containing the above-mentioned components in a flexible way using silicone rubber, and (b) an optical second made of a flexible material, preferably a polymeric material, most preferably silicone rubber. It may be housed in a multi-part shell. The first part may also be made of black plastic material, most preferably epoxy resin or PMMA. The shell may be molded on an industrial scale or handmade by methods known to those skilled in the art. First molding silicone rubber
When producing parts and optionally the second part, it is preferred to add colored powders (dyes) to the rubber. The shorter the wavelength, the greater the problem of external light. Therefore, the problem is
It may be minimized by adding dye to the material. The dye is preferably black, which minimizes interference from other light sources. The shell is fixed to the first part and the second part, for example by joining them, preferably by gluing them together, or by sticking them together in some other way, for example on the finger, toe or wrist. May be. Further, the shell may preferably have an inner bent portion and an inner contracted portion formed in the first portion thereof. In that case the fingers, toes or wrists are properly positioned during the measurement. The shell can take any shape and surrounds the internal bend or contraction. In this way the fingers, toes or wrists are tightened and the blood vessels are readily accessible for performing the method of the invention. The tightening may be done by mechanical means or simply by pressing by hand. For example, a thimble-like or handcuff-like device can be fixed and a measurement object can be tightened by using a tightening machine including a rubber band or a banding machine together with a tightening ring.

The flexible material of the first part of the shell may also be made of natural rubber or any flexible pure polymer or copolymer. Alternatively, the flexible material may consist of one or more polymers. The materials of the first and second parts are preferably free of allergenic substances, and therefore the thimble-like device is preferably sufficiently gentle on the skin of mammals. The shell allows the finger, toe or wrist to be measured to be clamped and preferably makes the vessel readily available for performing the method. The blood vessels are preferably arteries, veins or arterioles.
The detection is preferably performed on the wrist or the finger of the third phalange.

The handcuffed device according to embodiments of the present invention may be present as a flexible plastic patch, preferably fastened to a strap for fastening to the wrist. In that case the strap is locked this time using a locking device during the measurement to tighten the wrist. This embodiment is described in Figures 10 and 11. As can be seen in FIG. 10, the components are preferably arranged in an H-shape at the corners of a flexible, essentially rectangular patch. The patch preferably has rounded corners and a size of 51 × 35 mm. The patch preferably has a raised side for contacting the measuring range, eg human skin, at which the light source and the detector appear. The patch is preferably 51x35 mm in size and the raised portion is 31x47 mm in size, leaving a 2 mm margin for the outer dimension. As can be seen from FIG. 11, when the components are arranged in an H-shape, they are preferably fixed to the smaller rectangle, ie the shorter corner of 31 × 47 mm. The “H” is preferably tilted by about 90 degrees when viewed from the direction of the arm or the blood vessel during measurement on the wrist, for example.

The new device consists of at least 4 light-emitting diodes, preferably at least 6 light-emitting diodes and one detector, which form an H-shape around the detector and are handcuffed. Part of the structure is fixed to a patch this time to make it suitable for wrist measurements. In that case, the distance between the light source and the detector, based on the center of each component, is preferably 4 to 12 mm, most preferably about 8 to 9 m.
m. The light source and detector may be fixed to the edge of the patch containing the finger, toe or wrist. Preferably, the patch is a flexible plastic patch that is fastened to a strap for tying to the wrist. The strap includes a locking device. In addition, the device comprises a light source and a detector integrated in a patch, fixing the electrical components on one side of a black silicon coated printed circuit board card and the optical components on the other transparent side. Fix on the surface covered with silicon. This ensures electrical shielding, reduction of stray light and the possibility of sterilization. The patch is preferably rectangular with dimensions of 51 × 35 mm, and the light source and detector are arranged and fixed in an H shape at the corners of the patch.

The tubes in which blood characteristics are observed may be identified by proper selection of the separation between the light source and the detector. Theoretical analysis and experimental verification of the optical technique were described in two papers by I. Friedrin, K. Johansson and LG Lindberg. The article will be adopted and published in Physics in Medicine and Biology (Optical Non-Invasive Techniques I and II for Imaging the Tube, Faculty of Biomedical Engineering, Linkoping University, Sweden). The following is a summary of their analytical and experimental validation.

The reflection of light from human tissue depends on many parameters such as the wavelength of the light, the separation of the light source and detector, the size and diameter of the light source and detector, and the optical properties of blood and tissue. The separation between the light source and the detection fiber was varied at five center-to-center distances (2, 3, 4, 5 and 6 mm). The analysis was consistent with the earlier conclusion that a larger source and detector separation should be chosen to increase the effect of deeper tissue on the measured signal.

The results of the mathematical analysis and the results of the proven analysis can be summarized as follows. At higher separation values, the photons forming the maximum photon path and detected at the photodetector come from a deeper layer than for short distance values. This is shown in FIG. FIG. 9 is an explanatory diagram of separation of two different light sources and detectors and movement of photons at different FL (α) (FL (0) and FL (π / 2)). FL is the position of a set of fibers relative to the inside of the tube. Two positions of the light source and the fiber of the photodetector were considered in relation to the inside of the tube. The angle α is defined so as to show characteristics at different positions. The abbreviation FL (0) means that the light source and the photodetector are arranged in parallel, and FL (0)
π / 2) means that the light source and the photodetector are arranged perpendicular to the tube. Monte Carlo simulation shows that photons in the near infrared region for human tissue are
If the separation between the light source and the detector was about 2 mm, it was shown to penetrate about 2 mm before being detected.

Blood vessels in terms of vessels are measured at the level of three vessels in combination with a fixed fiber diameter (1 mm) according to the following: Surface level of blood vessels (about 1 mm). The level is sufficient to set the minimum distance between the illumination and detection fibers (2 mm during the experiment). Intermediate level of blood vessels (about 2 mm). The minimum distance between the illumination and the detection fiber is
The thickness is preferably 2-3 mm. Deep level of blood vessels (about 3 mm). The distance between the illumination and detection fibers is preferably greater than 3 mm.

The results of the above referenced paper show that it is possible to measure blood properties and physiological parameters such as oxygen saturation in selected vascular beds of veins or arteries. When measuring a thick part of the body such as the wrist or arm including the radial side, the distance between fibers (light source and detector) is 6 to 12 mm when relating to blood characteristics including Hb.
It is good to For thicker parts of the body such as the arms including the upper arm, the distance may be 12 to 30 mm. When measuring on the wrist or thicker part of the body,
It is preferable to apply pressure to the measurement site. The method according to the invention may also be used for measurements on tubes located below the ankle, including the back of the foot. Therefore, the present invention preferably includes a light source and a detector arranged at different distances set as described above according to the measurement range to be observed. By doing so, you can reach the target tube,
Therefore, it becomes possible to detect the blood characteristics including Hb. The distance between the detector and the light source is therefore preferably 1-20 mm, depending on the measuring range, as set out above.

The theoretical solution to the light distribution in the tissue described in the reference paper 2 is as follows:
It is the basis for describing how hemoglobin can be measured in reflection mode. Equation 32 in the article provides a general solution. In the equation, μ _a and μ _s represent the influence of the light ratio, and H and B or Z represent the influence on the pulsation variation in the blood vessel diameter during the heartbeat.

The light source is connected by a cord to a power supply which may be an oscillator. The oscillator may be connected to the amplifier and the LED driver. The driver may connect to one or more LEDs. A detector for reflection, eg a photodiode, is connected to at least one current / voltage converter. The converter may be connected to the amplifier as well. The signal passes through a bandpass filter and then becomes an analog output or through a μ controller connected to a readout device.

The device of the invention may further comprise a plurality of light sources, which may be in the form of rings, plates, cubes, spheres.
It may consist of a large matrix probe containing (six or more) and detectors (one or more).

The processor of the new device should be able to find the optimum measuring location of the tube, especially when using a matrix of multiple light sources and detectors. Moreover, the processor can reliably control / certify signal strength, perform algorithmic operations, evaluate data against stored standard curves, and display and display results with patient data and associated quality criteria. It may be used for storage. The output of the results from the implementation of the present invention may be performed by a connected printer device. The printer device may optionally be connected using visualization means.

A calibration curve may be used for carrying out the method according to the invention. A calibration curve stored in the memory of the processor, which is preferably part of the computer, provides the AC _R / A _{C R} or D obtained when the light beam is directed at the tube and then the reflection / reflection ratio is detected.
C R _/ DC _R denoted by may be reflected light intensity / reflected light intensity ratio of (%), it is possible to facilitate conversion to the hemoglobin value (mol / l). The calibration curve is preferably obtained simultaneously with the method according to the present invention by analyzing a blood sample collected from a healthy subject and a patient with a Hemocue device or a blood gas analyzer. In conjunction with the method, a spectrophotometric absorption curve in reflection mode or a recording curve in reflection mode may also be used.

Alternatively, of course, it is also possible to manually process the data to measure blood properties including hemoglobin. The results may also be visualized manually, for example by plotting the results in a figure. The signal from the detector may be analyzed using the following procedure.

Since the PPG signal is composed of two parts, the constant signal and the pulsation signal superimposed on the constant signal, the maximum and minimum points are first calculated. The maximum point is calculated by sweeping the time frame on the curve. The length of the time frame is adjusted to about 60% of its period according to the frequency of the AC signal (pulse), and is evenly distributed to the left and right. If there is no value larger than the central value within the time frame, the value is designated as the maximum point. afterwards,
To avoid the plateau formation curve being registered as a large number of maxima, the timeframe is moved rapidly by half the length of the timeframe. If there is a value within the time frame that exceeds the central value, the time frame is moved by one step. Calculate the minimum value in a similar manner.

For each minimum point, the AC height is calculated as the height from the minimum point between the two points to the connecting line between the maximum points closest to the left and right of the center point, respectively. Followed by 9
The median height of the AC heights is chosen as the representative value of the AC signal to eliminate artifacts that result in falsely detected minimum or maximum points. The DC signal is calculated as the total height to the reference minimum of the AC signal plus the AC signal. FIG. 14 shows an example of the procedure. Step d in the above summary of the invention preferably comprises the following steps. I) Sweep the time frame on the curve containing the detected values from transmission and / or reflection. The length of the time frame is preferably about 60% of the period and is evenly distributed left and right. II) If no value in the time frame is greater than the median value, the value is designated as the maximum point and the time frame is moved rapidly by half the length of the time frame, or the value is the median value. If it exceeds, the time frame is moved by only one step. III) Specify the minimum point in the same way as II) for the minimum value instead of the maximum value. The height of the IV) AC signal is obtained by subtracting the value on the vertical line of the minimum point located between the two points from the value on the connecting line including the two maximum points. V) Step IV) is repeated at least 8 times, the values from step IV) are tabulated and the sum is divided by the number of measurements to obtain the average AC value. VI) Optionally obtain a DC signal by adding the total height of the minimum of step IV) to the average AC signal of step V). Preferably said steps are carried out using a computer program for obtaining an AC signal and optionally a DC signal. The computer program for performing steps I) to IV) is preferably stored on a data storage medium. Preferably, the data storage medium is a processing unit or a part of the central processing unit shown in iV) of the summary of the invention, or a separate floppy disk inserted into the processing unit for use. The processing device may preferably comprise a computer program for carrying out the method according to the invention, eg as shown in the summary of the invention and / or in steps I to VI above.

The present invention also provides a computer program stored on a data storage device for carrying out the novel method, eg as set forth in the Summary of the Invention.

When measured on the skin, the above equations are the same, except that the light decreases in response to light absorption and light scattering in the tissue. Intensity may be compensated for by different blood flows when practicing the invention. When measuring the blood characteristics of blood in blood vessels located under the skin, the detection of reflected light is preferably performed on thick blood vessels, for example on the wrist or the finger of the third phalange.
However, the blood vessel must contain a blood volume that is significantly different from the surrounding blood volume consisting of capillaries. It should be noted that the method and device according to the present invention may be used to measure key blood characteristics, which are preferably represented by large blood vessels such as arteries. This may be done by compensating for the effects of blood pressure and blood flow on the measured intensity of the reflected light. The effects used in the method and apparatus according to the present invention may also be used to measure changes in blood characteristics in an individual or an extracorporeal system when the blood hemoglobin level is constant.

A further feature of the present invention is that the method and device is very simple for the detection of oxygen, as 97 to 98% of the total oxygen in human blood is transported by hemoglobin molecules in the blood. It means that you can. Of course, the method
Hemoglobin is normally incorporated into red blood cells unless the red blood cells are lysed, and thus may be used to measure the red blood cells themselves. Since the viscosity of blood corresponds to the amount of red blood cells in blood, the method may be used to measure viscosity. The method and apparatus of the present invention may also be used to measure hematocrit (HCT). The difference between hemoglobin, which is the number of hemoglobins per blood volume, and hematocrit, which is the amount of blood cells per blood volume, is measured by the intracellular hemoglobin concentration that determines the cell refractive index.

A variety of different blood constants are used for diagnosis. Some are interchangeable, and there is a generally accepted relationship between the constants. The generally accepted relationships are as follows:

[0059]   Constant index calculation   RBC Number of red blood cells per unit blood   EPC or red blood cell particle concentration   Hb hemoglobin concentration in blood   Hct hematocrit value or red blood cell Hct = RBCxMCV   EVF red blood cell volume content, total volume               Of red blood cell volume   MCV Erythrocyte volume MCV = EVF / RBC               Abbreviation for average particle volume   MCH Weight of hemoglobin in red blood cells MCH = Hb / RBC               Abbreviation for mean spherical hemoglobin   MCHC Hemoglobin concentration in erythrocytes MCHC = Hb / EVF               Abbreviation for average spherical hemoglobin concentration

Furthermore, human blood is made up of solid components and plasma. 3 for solid blood components
There are two basic types: red blood cells, white blood cells and platelets. Red blood cells contain hemoglobin, which carries oxygen from the lungs to the tissues of the body. Normal hemoglobin concentration in men is 13
2-163 gram / liter, female 116-148 gram / liter
Varies between. Hematocrit (Hct) is usually 39-49% (EVF 0
.39-0.49) and 37-44% (EVF 0.37-0.44) in women.
Between). White blood cells are about the same size as red blood cells, but do not contain hemoglobin. A healthy person has about 5,000,000 red blood cells per cubic millimeter of blood (the human body contains about 5 liters of blood) and about 7,500 white blood cells per cubic millimeter of blood. . Therefore, a healthy person will have about 1 white blood cell for every 670 red blood cells circulating in the vascular system. White blood cells
It is responsible for the immune system of mammals, preferably humans, eg some leukocytes swallow invading pathogens.

Regarding platelets, platelets are the smallest of the solid blood cell components, usually less than 1 μm in diameter. Platelets are less common than red blood cells, but more common than white blood cells. A healthy person has about 1 platelet for every 17 red blood cells that circulate in a total of about 2 trillion vasculature.

In summary, the method and apparatus according to the present invention, when indirectly measuring the amount of white blood cells and / or platelets, uses known relationships between parameters to measure various properties of the vasculature. Can be used for For white blood cells, the coefficient is 1/670 of red blood cells, and for platelets, the coefficient is 1/17 of red blood cells. Therefore, the blood characteristics in steps iii and iv in the method and device according to the invention respectively also include white blood cells and / or platelets. Cholesterol and albumin concentrations can also be measured by using a known hemoglobin concentration together with the method described in GB2329015 as a reference. The methods described in the above references relate to non-invasive measurement of blood constituent concentrations.

The device and method according to the invention also enable the diagnosis of asymmetry or disease in mammals, for example anemia of red blood cell deficiency. Binge eating patients often suffer from anemia. In addition, congestive heart failure and cardiac arythmies are also
Detection may be performed using the method and apparatus according to the present invention. The method and device according to the invention have the potential for indirect measurement of platelet disorders such as thrombocytopenia.
This can indicate problems with menstrual depression and condensation. In addition, high levels of white blood cells suggest viral infection. Leukocytosis and leukopenia are also possible signs and can be detected indirectly. Also, other diseases of the phagocyte system and the immune system are detectable. Neonatal surveillance is another area of application of the invention. Surgical monitoring is also a possible application. The device compensates for stable, interactive effects (skin color, lipids, etc.), thus providing a "zero-level" at the beginning of surgery.
Therefore, it is possible to easily monitor the blood characteristics including hemoglobin.

The present invention also allows accurate measurement of a patient's blood without the risks associated with blood collection (eg, AIDS, hepatitis A, B and C, etc.). Blood collection with a needle is a painful method, especially for individuals who need to take large numbers of blood samples. The drawbacks can be eliminated by using the method and the device according to the invention. Moreover, the method and device according to the invention are particularly suitable for measurements in children.

The following examples illustrate embodiments of the present invention, but are not intended to limit the scope of the invention in any way.

Example 1 Detection was performed using the following apparatus. One tube with an inner diameter of 3 mm made of acrylic glass (PMMA). Two optical fibers with a diameter of 0.094 mm. One of the fibers was for transmitting light (light source) and the other was for receiving reflection of light (photodetector). One glass tube with an outer diameter of 0.210 mm for accommodating optical fibers arranged parallel to each other. Whole blood from a blood donor pumped through a PMMA tube.

FIG. 1 schematically shows a flow model for the detection of light reflection. FIG. 2 shows the orientation of red blood cells at intermediate levels of shear rate. FIG. 3 shows the light absorption in blood by different absorbing substances. FIG. 4 shows light scattering by red blood cells.

The results of the above experiments show that the light is diffused in a specific direction when it hits the red blood cells in the tube. This is probably due to the shape of the blood cells which orients them in different directions as they move through the circular tube, ie the biconcave disc shape. This is demonstrated by the optical technique of placing two optical fibers in a small catheter. In this case, one optical fiber acts as a light source and the other optical fiber acts as a photodetector. The fiber pair is moved from one periphery to the other at the cut surface of the circular tube.

FIG. 5 and FIG. 6 are the outline of the experimental results, that is, the intensity of the light transmitted through the red blood cells flowing through the acrylic glass tube. The experimental equipment is the same as that of the above experiment.

FIG. 5 shows the relative change in transmitted light with respect to blood flow for two different types of red blood cells. "Stiff cells" are treated with glutaraldehyde to produce stiff cells.
(stiff) red blood cells. That is, the red blood cells have lost the ability to change shape upon pressure from the flow.

The results show that one of the important properties of red blood cells is flexibility. This results in a change in shape with increasing flow, as evidenced by a reduced permeation intensity for increasing flow, ie elongation and orientation. Inflexible, or stiff, red blood cells show little or no orientation effect on the flow as measured by changes in light transmission.

FIG. 6 shows the relative change in transmitted light intensity with respect to blood flow for two types of blood cells. "Globular blood cells" are red blood cells that have been treated with a non-isotonic buffer. By the above processing,
Blood cells loosen the biconcave disk shape. This results in intimate contact and orientation for increasing flow, as evidenced by a reduced transmission intensity for increasing flow. As the measured light transmission changes, spherical red blood cells show reduced shear stress for increasing flow and little or no orientation effect for flow.

It can therefore be concluded that the orientation of red blood cells as a function of flow in human and mammalian flexible or inflexible ducts or arteries is mainly due to the unique biconcave disc shape and flexibility. .

Example 2 The second experimental equipment basically consisted of the following. The three main parts are basically as follows. Rigid flow-through model connected to a light source and photodetector via a cylindrical disc oxygenator, flow control roller pump (peristaltic pump) and optical fiber that also serve as a blood reservoir

The experimental setup is basically shown in FIG. However, one photodetector is missing because it measures both transmission and reflection. A corrugator regulated a roller pump that produced continuous blood flow. The pressure transducer is also one of the blood circulation circuits.
It was a department. The temperature of blood can be controlled by circulating hot air around the experimental equipment.
The temperature was kept constant at 0.0 ± 0.1 ° C.

The gas mixture was introduced into a reservoir and mixed with blood. Gas exchange was simulated with a disc oxygenator and the gas mixture consisted of 19% oxygen and 5.6% carbon dioxide in nitrogen. Oxygen saturation was kept at 98-99% and blood gas parameters (p
O ₂ , pCO ₂ and pH) were assumed not to deviate from normal physiological values.

A layered flow-through model was used to minimize red blood cell hemolysis. The wavelength used was 800 nm, and the isosbestic point at which the minimum absorption of light occurs in red blood cells. Measurement
A tube made of acrylic glass having an inner diameter of 3.0 mm was used.

Example 3 A handcuff-like test device comprising a shell, which is one of the preferred embodiments of the present invention shown in FIG. 10, was used. The handcuff device consists of I) 6 light sources (LED, λ = 875 nm) and II) 1 detector.

The handcuffs consist of a patch of flexible material and a strap. The flexible material consists of silicone rubber with black dye (non-conducting ceramic pigment).
The flexible material may form bends, for example for the wrist, fingers or toes. PP
G-sensors were designed specifically for use on the wrist. The optical geometry of the sensor was optimized to allow observation of blood properties, preferably blood flow deep into the tissue from the radial artery over the flat portion of the radius. The center-to-center distance between the LED and the photodetector is about 8-9 mm.

All components are contained in a sensor with electronics on one side of a printed circuit board card coated with black silicon and optics on the other side coated with clear silicon. This ensures electrical insulation, reduction of stray light and the possibility of sterilization.

The way to connect the power source of the handcuff-like device and the battery eliminator is shown in FIG. 10 through a block diagram schematically illustrated. The handcuffs are further connected to a laptop computer which stores all measurement signals.

The measurement was performed using the probe (see FIG. 12) held on the wrist of the subject. The probe was placed on the wrist above the radial artery. Saline was injected in the flow direction near the probe. The arterial needle was inserted into the radial artery in the flow direction at a position of 10 cm to the hand. The distance between the sensor and the tip of the needle was about 5 cm. Saline was infused at different volumes for 1-5 seconds. The PPG signal was recorded and the monitoring depth was confirmed.

Clinically recorded PPG signals were recorded in patients with heart failure at the same time as ECG recordings.
Only the intensity of the reflected light was recorded. The change in signal corresponded to the dilution effect in the blood. The result is that there are two components, in other words, the pulsatile component (AC) that is synchronous with the heartbeat.
And a PPG signal consisting of a slowly varying component (DC) can be seen in FIG. In the figure, the light reflection can be seen by the change in both AC and DC signals corresponding to the dilution effect in the blood after a delay of approximately 0.5 seconds. From this it can be seen that the device according to the invention can be used to extract information from the radial artery itself. The bottom two panels of FIG. 12 are records for a patient with atrial fibrillation. The AC and PPG signals (upper curve) were consistent with the irregular appearance of the QRS complex on the electrocardiogram. The DC component reflects different physiological features in the circulation, such as changes in total blood volume such as vasomotion, thermoregulation and respiration.

Thus, the device according to the invention is useful, for example, for observing blood flow associated with the center on the wrist. The changes in the signal in the amplitude, curve shape and frequency attributes may further reflect different pathological phenomena in the body corresponding to congestive heart failure and cardiac rhythm thms. Other telemetric (t
elemetrical) applications are conceivable for the device and method according to the invention.

Like other blood flow monitoring systems, the device of the present invention is also susceptible to patient hand movements. Loops may also be incorporated into the device to reduce artifacts. In addition to the blood flow parameters described above, means for monitoring blood pressure, heart rate, respiration rate and oxygen saturation may be incorporated into the device.

Example 4 Measurement was performed using the apparatus according to the present invention. The relative pressure was observed and the result can be seen in FIG. The diagram in FIG. 8 shows the intensity of reflected pulsatile light with increasing systolic pressure. Diastolic pressure was kept constant.

While various embodiments of the invention have been described above, those of skill in the art will further recognize minor modifications that are within the scope of the invention. The breadth and scope of the present invention should not be limited by the exemplary embodiments described above, but should be defined only according to the claims and their equivalents.

[Brief description of drawings]

FIG. 1 shows a schematic flow model for light reflection detection.

FIG. 2 illustrates the orientation of red blood cells at intermediate levels of shear rate.

FIG. 3 is a diagram showing light absorption in blood by different absorbing substances.

FIG. 4 is a diagram showing light scattering by red blood cells.

FIG. 5 shows the relative change in transmitted light with respect to blood flow for two different types of red blood cells.

FIG. 6 shows the relative change in transmitted light intensity with respect to blood flow for two types of blood cells.

FIG. 7 is a diagram basically showing experimental equipment of an example (Example 2).

FIG. 8 shows the results from the relative pressure observed as in Example 4.

FIG. 9 shows photons with a larger separation value that form the largest photon path and are detected by a photodetector resulting from a deeper layer than for a smaller separation value.

FIG. 10 shows the probe of the device of the present invention placed on the radial artery of the wrist of a subject.

FIG. 11 is a view showing a probe made of a patch made of a flexible material.

FIG. 12 is a view showing three views for explaining physiological saline injected in the flow direction close to the probe of FIGS. 10 and 11. Only the intensity of the reflected light was recorded, the change in signal corresponding to the dilution effect in blood. The bottom two views of FIG. 12 show a patient record of atrial fibrillation, ie PPG and ECG signals.

FIG. 13 is a diagram illustrating the device of the present invention for measuring blood characteristics comprising a Bluetooth device that does not require a cable for wireless communication of data between distant components of the device of the present invention. is there.

FIG. 14 is a diagram showing a PPG signal together with a DC signal, an AC signal, a minimum point and a maximum point.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Magnus Wegfosch             Sweden, S-582 45 Linchepi             Hungary's Gartan No. 15 F term (reference) 2G059 AA05 AA06 BB12 CC16 EE02                       EE11 GG02 GG03 HH01 HH02                       HH06 JJ17 KK01 KK03 MM01                       MM03 MM10 MM12 PP06                 4C038 KL05 KL07

Claims (39)

[Claims] 1. A non-invasive measurement method for measuring blood characteristics including hemoglobin from a mixture of liquid and blood cells contained in a light-transmitting tube, comprising: a) applying a first light beam and a second light beam having different wavelengths to each other. A step of directing to the transparent tube, b) a step of detecting the light intensities of the first and second light beams reflected from the transparent tube, c) a step of calculating a ratio of detected intensities, and d) A non-invasive measurement method comprising a step of analyzing a ratio to measure a blood characteristic. 2. The wavelength of the first light beam is selected such that the light absorption of the red blood cells is relatively small when the first light beam passes through the red blood cells, while the wavelength of the second light beam is set to the second light beam. The method of claim 1, wherein the light absorption of the red blood cells is selected to be relatively large and large as the light beam passes through the red blood cells. 3. A method according to claim 2, characterized in that the wavelength of each light beam is selected in the range of 200 nm to 2000 nm, preferably 400 nm to 1500 nm. 4. The wavelength of the first light beam is selected within the range of 770 nm to 950 nm, preferably 770, 800, 850, 940 or 950 nm, and the second
The wavelength of the light beam is selected within the range of 480 nm to 590 nm, preferably 50
The method according to claim 3, wherein the method is 0 nm. 5. The method according to claim 1, wherein the first and second light beams are directed parallel to each other. 6. The intensity of the reflected light of the first and second light beams is detected with respect to the light-transmitting tube between the first and second light beams, respectively. The method described in. 7. A method as claimed in any one of the preceding claims, characterized in that the first and second light beams are each directed essentially perpendicular to the light-transmitting tube. 8. The method according to claim 1, wherein step (c) is carried out while a mixture of liquid and blood cells is flowing through the light-transmitting tube. 9. The method according to claim 1, wherein the mixture of liquid and blood cells comprises plasma. 10. The method according to any one of claims 1 to 9, characterized in that steps (a) and (b) are performed on a mammalian, preferably human blood vessel. 11. Steps (a) and (b) are performed on a blood vessel having a diameter of greater than 0.1 mm,
11. Method according to claim 10, characterized in that it is preferably performed on veins, arteries or arterioles. 12. A method according to claim 10 or 11, characterized in that steps (a) and (b) are performed on the wrist, toes or fingers, preferably on the wrist or the finger on the third phalange. 13. The method according to claim 1, wherein steps (a) and (b) are carried out in a tube of a dialysis machine, a slaughterhouse apparatus or a blood fractionation apparatus, or a tube consisting of a blood bag. The method described in Kaichi. 14. A detection intensity value of reflected light of each of the first and second light beams,
Transmitting wirelessly to the means for performing steps (c) and (d).
The method according to any one of. 15. The method according to claim 14, wherein the wireless transmission is performed by using a communication channel compliant with the Bluetooth (registered trademark) standard. 16. The step (c) comprises the step of: I) searching for a curve drawn by the detected values of the light intensity, which is equally divided into left and right, in a time frame having a length of about 60% of the cycle. II) If no value in the time frame is higher than the median value, move the time frame by half the length of the time frame with that value as the maximum point, and if the value exceeds the median value, the time Step of moving the frame by one step, III) Step of designating the minimum point in the same way as II) for the minimum value instead of the maximum value, IV) From the value on the connecting line including the two maximum points, there is between them The step of obtaining the height of the AC signal by subtracting the value on the perpendicular of the minimum point, V) step IV) is repeated at least 8 times, the values obtained in IV) are added, and the sum is divided by the number of observations Obtaining the signal mean value, and VI) If desired, add the total height of the minimum point of IV) to the AC signal mean value of step V) and D
Method according to claim 1, characterized in that it comprises the step of obtaining a C signal, preferably using a computer program for obtaining said AC signal and optionally a DC signal. 17. An apparatus for measuring blood characteristics including hemoglobin from a mixture of liquid and blood cells contained in a light-transmitting tube, wherein the first light beam and the second light beam having different wavelengths are supplied to the light-transmitting tube. A first light source and a second light source which are respectively directed, at least one detector for detecting the light intensities of the first and second light beams reflected from the light-transmitting tube, and a ratio of the detected intensities is calculated, An apparatus comprising a processing device for analyzing the ratio to measure blood characteristics. 18. The apparatus according to claim 17, further comprising recording means for storing the value of the measured blood characteristic. 19. Apparatus according to claim 17 or 18, characterized in that it further comprises means for visualizing measured blood properties. 20. The first light source emits light of a wavelength that is essentially not absorbed by red blood cells, and the second light source emits light of a wavelength that is basically absorbed by red blood cells. 20. The device according to any one of 19 to 19; 21. Each light source comprises 200 nm to 2000 nm, preferably 400 nm
21. The device of claim 20, emitting light having a wavelength in the range of nm-1500 nm. 22. The wavelength of the light emitted by the first light source is 770 nm to 950 nm.
, Preferably 770, 800, 850, 940 or 950 nm,
22. Device according to claim 21, characterized in that the wavelength of the light emitted by the second light source is in the range 480 nm to 590 nm, preferably 500 nm. 23. The device according to claim 17, wherein the first and second light sources emit their first and second light beams parallel to each other. 24. The detector is arranged between the first and second light sources to detect the intensities of the reflected lights of the first and second light beams, respectively. The apparatus according to any one of 1. 25. The first and second light sources each direct the first and second light beams essentially perpendicularly to the light-transmitting tube, as claimed in any one of claims 17 to 24. Equipment. 26. The device according to any one of claims 17 to 25, wherein the mixture of liquid and blood cells contains plasma. 27. A method according to any one of claims 17 to 26, characterized in that the light source and the detector are integrated in a test device designed for non-invasive application to the blood vessels of mammals, preferably humans. The device according to claim 1. 28. The device of claim 27, wherein the test device is configured to fit a wrist, toe or finger. 29. The device according to claim 28, wherein the test device comprises a thimble-like shell applied to a finger or toe. 30. The device according to claim 29, wherein the shell forms a clamp, on which the detector and at least one first and second light source are arranged. 31. A communication means for wireless communication between the various components of the device, including the light source, the detector and the processing device, further comprising communication means.
The apparatus according to any one of 1. 32. The device of claim 18, comprising communication means for wireless communication between various components of the device, including the light source, detector, processing device, recording means and visualization means. . 33. An apparatus according to claim 31 or 32, wherein the communication means includes individual modules for transmitting and receiving signals. 34. The device of claim 33, wherein the module is capable of transmitting and receiving signals using a communication path conforming to the Bluetooth (registered trademark) standard. 35. The light source comprises a light emitting diode, and a distance between each diode and the detector is 4 to 12 mm as a center distance between the diode and the detector.
A device according to any one of claims 17 to 26, characterized in that it is preferably 8-9 mm. 36. The device according to claim 17, wherein the processing device is adapted to convert the detected intensity value into the concentration value of the measured blood characteristic. 37. The processing apparatus comprises steps (c) and (d) of the method according to claim 1.
37. A device according to any one of claims 17 to 36, characterized in that 38. A computer program stored on a data storage medium for performing steps (c) and (d) of the method according to claim 1. 39. Use of the device according to any one of claims 17 to 37 in a dialysis machine.